Synthesis of irbesartan

ABSTRACT

Provided are a method of making irbesartan via a Suzuki coupling reaction and a novel intermediate, 2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one, for such process. The novel process includes the step of reacting such intermediate with a protected imidazolephenylboronic acid.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 10/759,906filed Jan. 16, 2004, now U.S. Pat. No. 7,019,148 which claims benefitsof U.S. Provisional Application No. 60/440,997 filed Jan. 16, 2003 thecontents of which are incorporated herein.

The present invention relates to a novel synthesis of irbesartan.

BACKGROUND OF THE INVENTION

Irbesartan is a known angiotensin II receptor antagonist (blocker).Angiotensin is an important participant in therenin-angiotensin-aldosterone system (RAAS) and has a strong influenceon blood pressure. The structure of irbesartan is shown below (I).

The synthesis of irbesartan is discussed, inter alia, in U.S. Pat. Nos.5,270,317 and 5,559,233; both of which are incorporated herein in theirentirety by reference. In the synthesis therein disclosed, theprepenultimate reaction step (exclusive of work-up and purification)involves the reaction of a cyano group on the biphenyl ring with anazide, for example tributyltin azide. Reaction time as long as 210 hourscan be required. See, e.g., '317 patent.

U.S. Pat. No. 5,629,331 also discloses a synthesis of irbesartan from aprecursor 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-ene-4one with sodium azide using a dipolar aprotic solvent.As acknowledged in the '331 patent, there are safety risks involved inthe use of azides (column 4, line 39). Also, dipolar aprotic solvents(e.g. methylpyrrolidone) are relatively high boiling and can bedifficult to remove.

There is a need for an improved synthetic route to irbesartan.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a method of making2-butyl-3-[[2′-(1-trityl-1H-tetrazol-5-yl)biphen-4-yl]methyl]1,3-diazaspiro[4.4]non-1-one(IRB-03) including the steps of reacting2-butyl-3-(4′-bromophenyl)-1,3-diazaspiro[4.4]non-1-ene-4-one (IRB-05)with 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid (IRB-07) in thepresence of a first solvent, especially tetrahydrofuran (THF) ordimethoxyethane, a second solvent, especially water, particularlycombined with a base, and a catalyst that includes especially apalladium complex, e.g., Pd(O(O)CCH₃)₂ and a phosphine, especially atriarylphosphine, e.g. triphenyl phosphine (PPh₃).

In another aspect, the present invention relates to a process for makinga 3-(haloaryl)-1,3-diazaspiro[4.4]non-1-ene-4-one compound, especially3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one, including thestep of reacting (combining), in the presence of a phase transfercatalyst (e.g. tetrabutylammonium sulfate), an acid addition salt,especially a hydrochloride, of 1,3-diazaspiro[4.4]non-1-ene-4-one with ahaloaryl compound, especially a bromobenzyl halide compound (e.g.4-bromobenzyl), in a solvent system including a first solvent,especially an aromatic hydrocarbon, and a second solvent, especiallybrine containing a base.

In another aspect, the present invention relates to the compound2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one,especially when prepared according to the forgoing process.

In still a further aspect, the present invention relates to a method ofmaking a 5-phenyl-1-trityl-1H-tetrazole compound including the step ofreacting 5-phenyl-1-H-tetrazole with chlorotriphenylmethane (tritylchloride) in a solvent, especially tetrahydrofuran, in the presence of abase, especially triethylamine.

In yet another aspect, the present invention relates to a method ofmaking 2-(tetrazol-5-yl)phenylboronic acid including the step ofreacting 5-phenyl-1-trityl-1H-tetrazole with a borate, especially atrialkyl borate (e.g. tri-isopropyl borate) in a solvent, especiallytetrahydrofuran, and in the presence of a base, especiallyn-butyllithium.

In still yet another aspect, the present invention relates to a methodof making irbesartan that includes the step of reacting2-butyl-3-(4′bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one with2(1-trityl-1H-tetrazol-5-yl)phenylboronic acid in a two-phase solventsystem having a first solvent, especially THF or dimethoxyethane or amixture of these, and a second solvent, especially water, in thepresence of a catalyst, especially a palladium complex or a nickelcomplex.

In a further aspect, the present invention relates to a process ofmaking irbesartan that includes the step of reacting an acid additionsalt, especially the hydrochloride, of2-butyl-1,3-diazaspiro[4.4]non-1-ene-4-one with a haloaryl compound,especially 4-bromobenzyl bromide in the presence of a base, especiallyKOH or NaOH, in a two-phase solvent system having a first solvent,especially toluene, and a second solvent, especially water or brine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel synthesis of irbesartan andanalogues thereof, including the step of reacting a2-(5-tetrazoyl)phenylboronic acid with a3-(haloaryl)-1,3-diazaspiro[4.4]non-1-ene-4-one. The step is carried outin the presence of a palladium or nickel catalyst. Such a synthetic stepis known by one of skill in the art as a Suzuki coupling reaction. See,e.g., N. Miyaura et al., Tetrahedron Letters 1979, 3437. See also, N.Miyaura, A. Suzuki, Chem. Commun. 1979, 866. The step can be carried outin a two-phase reaction system having first and second liquid phases.

The first and second phases include first and second solvents,respectively, which are substantially immiscible in each other so that,when combined in a reaction vessel, a two-phase system is formed.Solvents are substantially immiscible in each other when equal volumesof them are mixed together, a two-phase system is formed in which thevolume of the two phases is essentially equal. Preferably, substantiallyimmiscible solvents are soluble in each other to the extent of about 1%(weight basis) or less.

The first solvents are organic solvents. Examples of preferred organicsolvents include, but are not limited to: ether solvents such as1,2-dimethoxyethane (DME), diethoxymethane, (glymes), andtetrahydrofuran (THF); formals such as diethyl formal; and hydrocarbonsolvents such as, toluene, m-xylene, o-xylene, the tetralins; andmixtures of any of the foregoing. Other hydrocarbons useful as firstsolvents in the practice of the present invention will be apparent tothe skilled artisan. Diethyl formal is the preferred formal.1,2-dimethoxyethane (DME) is the preferred glyme and is particularlypreferred as an ether first solvent, especially in combination with THFwhen the catalyst includes a palladium complex.

The second solvent can be water, or, preferably, an inorganic basecombined with water. When an inorganic base is used, the preferredinorganic base is potassium carbonate. Potassium hydroxide and sodiumhydroxide are other examples of inorganic bases.

The novel synthesis of irbesartan, and analogues thereof, of the presentinvention includes the step of reacting a protected (e.g. tritylated)2-(5-tetrazoyl)phenylboronic acid with a3-haloaryl-1,3diazaspiro[4.4]non-1-ene-4-one. A preferred2-(5-tetrazoyl)phenylboronic acid is2-(5-(1-trityl-1H-tetrazole))phenylboronic acid (IRB-07), Structure II.A preferred 3-haloaryl-1,3-diazaspiro[4.4]non-1-ene-3-4-one is2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-3-one (IRB-05),Structure III.

The step is carried out in a two-phase reaction system having first andsecond liquid phases.

A catalyst is combined with the first liquid phase, preferably includingan ether solvent. Any known catalyst for the Suzuki reaction can beused. Preferably, the catalyst is selected from palladium and nickelcomplexes. Most preferred catalysts include Pd(O(O)CCH₃)₂, Pd Cl₂ andNiCl₂. When a palladium complex such as Pd(O(O)CCH₃)₂ [e.g. PdOAc₂] isused, the catalyst also includes a triaryl phosphine, especiallytriphenyl phosphine. When the catalyst includes a palladium complex, thefirst solvent preferably includes an ether solvent, like DME, that canform a complex with Pd.

As described above, the first liquid phase is an organic solvent phase,most preferably and particularly when the catalyst includes a palladiumcomplex, the first liquid phase is a mixture of 1,2-dimethoxyethane andTHF. The ratio of 1,2-dimethoxyethane: THF can be from about 10:1 toabout 1:5, the most preferred ratio of 1,2-dimethoxyethane: THF is fromabout 6:1 to about 2:1. The reaction is carried out in the presence of acatalyst.

Subsequently, IRB-07 is combined with the solvent mixture. Water, abase, and IRB-05 are added, preferentially sequentially, to the reactionmixture, and a two-phase reaction system having a first organic solventphase and a second aqueous phase is formed. The reaction mixture isheated under reflux conditions for a reaction time of between 2 to 4hours.

After the reaction time, the reaction mixture is allowed to cool, andthe two phases are separated. If desired, the aqueous phase can beextracted one or more times with toluene and the extract(s) combinedwith the first (aromatic hydrocarbon) phase. The first phase isevaporated to obtain crude residue of product IRB-03.

In embodiments in which 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid,(IRB-07), is the phenylboronic acid, the synthetic method of the presentinvention can and preferably does include a further step in which thetrityl group is cleaved from the tetrazole ring to produce irbesartan(IRB-00), or an analogue thereof. Crude residue produced in thesynthetic step described above is dissolved in a suitable water-misciblesolvent. A solvent is water miscible if it is miscible with water atleast in any proportion from 80:20 to 20:80 (weight basis). Acetone is apreferred water-miscible solvent. The resulting solution is acidifiedand agitated at a temperature between about 15° C. and about 30° C. Thetime of the cleavage reaction can be conveniently monitored using thinlayer chromatography. The acid is neutralized with a molar excess ofbase, preferably aqueous KOH or NaOH, and the water-miscible solvent isevaporated, preferably at reduced pressure. The trityl alcohol formed isseparated and the liquid phase is acidified (e.g. to a pH of about 4),preferably with mineral acid, most preferably with HCl or H₂SO₄. Theresulting suspension is cooled and the product recovered by, forexample, filtration. If desired, the isolated product can be washed withan organic solvent, preferably a lower aliphatic alcohol, mostpreferably iso-propanol or butanol, and dried, preferably at reducedpressure.

The 2-(5-tetrazoyl)phenylboronic acid and1,3-diazaspiro[4.4]non-1-ene-3-(haloaryl)-4-one which are reacted in themethod of the present invention to produce irbesartan or an analoguethereof, can be prepared by methods known in the art, or by thefollowing synthetic procedures.

The 2-(tetrazol-5-yl)phenylboronic acid can be prepared by firstreacting a 5-phenyl-1H-tetrazole with chlorotriphenylmethane in thepresence of a base, especially an amine (e.g. triethylamine) in asuitable solvent system to provide a 5-phenyl-1-trityl-1H-tetrazole. Apreferred 5-phenyl-1-trityl-1H-tetrazole is IRB-06 (structure shown inExamples). Suitable solvents for the solvent system include organicsolvents. A particularly preferred solvent system is a mixture of THFand triethyl amine as the base. Following removal of by-products, the5-phenyl-1-trityl-1H-tetrazole, such as IRB-06, can be isolated prior touse in the next step of the synthesis, or used in solution form. Theprotected tetrazole so formed is subsequently reacted with a suitableborate in the presence of a base, to form the desired boronic acidderivative, such as 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid(IRB-07; structure shown in Examples). The reaction is carried out insolution, preferably in an organic solvent. The organic solvent is mostpreferably THF. Suitable bases will be apparent to the skilled artisan.A preferred base is butyllithium. The preparation can be at any suitabletemperature, preferably at a temperature lower than about −20° C. Thereaction is allowed to proceed for a time that the skilled artisan willknow to adjust according to the reaction temperature.

The 3-haloaryl-1,3-diazaspiro[4.4]non-1-ene-4-one can be prepared bycombining a 1,3-diazaspiro[4.4]non-1-ene-4-one acid addition salt,preferably a hydrochloride salt, with a haloaryl compound. A preferred1,3-diazaspiro[4.4]non-1-ene-4-one acid addition salt is2-butyl-1,3-diazaspiro[4.4]non-1-ene-4-one hydrochloride (IRB-01). Apreferred haloaryl compound is 4-bromobenzyl bromide. Reaction of2-butyl-1,3-diazaspiro [4.4]non-1-ene-4-one hydrochloride (IRB-01) with4-bromobenzyl bromide leads to the production of2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one (IRB-05).2-Butyl-1,3-diazaspiro[4.4]non-1-ene-4-one is known in the art and isdisclosed, for example, in U.S. Pat. No. 5,559,233, which isincorporated herein by reference.

The reaction is carried out in a two-phase reaction system having firstand second liquid phases.

A first liquid phase comprising the haloaryl compound and a phasetransfer catalyst in a suitable solvent is prepared. The solvent may bean organic solvent. A most preferred solvent is toluene.

Phase transfer catalysts are well known to one skilled in the art oforganic synthesis. Phase transfer catalysts are of particular utilitywhen at least first and second compounds to be reacted with each otherhave such different solubility characteristics that there is nopractical common solvent for them and, accordingly, combining a solventfor one of them with a solvent for the other of them results in atwo-phase system.

Typically, when such compounds are to be reacted, the first reactant isdissolved in a first solvent and the second reactant is dissolved in asecond solvent. Because the solvent for the first reactant isessentially insoluble in the solvent for the second reactant, atwo-phase system is formed and reaction occurs at the interface betweenthe two phases. The rate of such an interfacial reaction can be greatlyincreased by use of a phase transfer catalyst (PTC).

Several classes of compounds are known to be capable of acting as phasetransfer catalysts, for example quaternary ammonium compounds andphosphonium compounds, to mention just two. Tetrabutylaminoniumhydrogensulfate is a preferred PTC for use in the practice of presentinvention.

A second liquid phase comprising a 1,3-diazaspiro[4.4]non-1-ene-4-oneacid addition salt, water and a base, preferably an inorganic base, mostpreferably, KOH. The base is present in an amount between about 1 andabout 6 molar equivalents relative to the number of moles of1,3-diazaspiro[4.4]non-1-ene-4-one acid salt.

The first and second solutions are combined to form a reaction system(mixture) that has first and second phases. The combining can be in anysuitable vessel that is equipped with means for vigorous agitation ofthe reaction system to maximize the interfacial area between the twophases. The combining can be at any temperature from about 20° C. toabout 95° C., preferably at about 90° C. The reaction is allowed toproceed in the two phase system for a time that the skilled artisan willknown to adjust according to the reaction temperature. When the reactiontemperature is about 90° C., a reaction time between about 1 and about 2hours is usually sufficient.

After the reaction time, the reaction system is allowed to cool, the twophases are separated. If desired, the aqueous phase can be extracted oneor more times with toluene and the extract(s) combined with the first(aromatic hydrocarbon) phase. The first phase is evaporated to obtaincrude residue.

The present invention can be illustrated in one of its embodiments bythe following non-limiting example.

Example 1A. Preparation of IRB-05

Weight; Mw volume Mmol Eq. IRB-01 230.73 57.7 g 250 1.25 4-Bromobenzylbromide 249.49 50.0 g 200 1.0 Potassium hydroxide, 85% 56.11 49.6 g 7503.75 Water  200 mL Bu₄NHSO₄ 339.54  8.5 g 0.125 Toluene  800 mL

To a preheated (90° C.) solution of 4-bromobenzyl bromide and phasetransfer catalyst (Bu₄NHS0₄) in toluene was added a prestirred (40 minat room temperature) solution of KOH and IRB-01 in water. The resultingtwo-phase mixture was heated for 1 hour at 90° C. with vigorousstirring. The mixture was cooled to room temperature, water (500 mL) wasadded and the mixture was stirred for additional 30 min. The phases wereseparated and the aqueous phase was extracted with an additional portionof toluene (100 mL). The combined organic portions were washed withwater and brine, dried over Na₂SO₄ and evaporated under reducedpressure. 74.0 g of IRB-05 was obtained as a colorless oil. The yieldwas 94%, with a purity of 94%.

Example 1B. Preparation of IRB-06

Weight; Mw volume Mmol Eq. 5-Phenyl-1H-tetrazol 146.15  56.0 g 383 1.0Chlorotriphenylmethane 278.78 112.0 g 402 1.05 Et₃N 101.2  61.0 ml, 4401.15 THF   400 mL

To a solution of 5-phenyl-lH-tetrazol and triethylamine in dry THF wasadded, in one portion, chlorotriphenylmethane. The reaction was slightlyexothermic, about 40° C. The resulting suspension was stirred underargon for 2 hours (TLC monitoring; Hex/EtOAc 4:1). The mixture wascooled to 0° C., stirred for 30 min and the precipitatedtriethylammonium chloride was filtered and washed with cold THF (100mL). The filtrate was evaporated under reduced pressure and the yellowsolid residue (approx. 180 g) was crystallized from acetonitrile (800mL) to give 141.5 g. The yield was 94%, with a purity of 94%.

Example 1C. Preparation of 2-(5-(1-trityl-1H-tetrazol)phenylboronic acid(IRB-07)

Weight, Mw volume mmol Eq. IRB-06 388.46 39.0 g 100 1.0 BuLi (1.6 M inhexane) 75.0 mL 120 1.2 Triisopropyl borate 188.08 30.0 mL 130 1.3 THF 250 mL

The solution of 5-phenyl-1-trityl-1H-tetrazole (IRB-06) in dry THF(Prepared in Example 1B) was cooled to −20° C. under Argon. Traces ofwater were quenched with n-butyllithium (approx. 5 mL). When the mixtureremained red for 5 minutes the addition was stopped. The main charge ofn-butyllithium was then added dropwise at temperature below −15° C. andthe resulting red suspension was stirred for additional 30 minutes at−20° C. The mixture was cooled to −30° C., and triisopropyl borate wasslowly added, with the reaction temperature maintained at below −20° C.At this point, the slurry was dissolved and the resulting red solutionwas stirred for 30 minutes at −25° C., and then warmed to roomtemperature over 40 minutes. The solvents were evaporated under reducedpressure and the yellow semisolid residue was extracted with isopropylalcohol (IPA) (200 mL) and cooled to 0° C. Saturated aqueous NH₄Cl (40mL, approx. 180 mmol) was slowly added, keeping the temperature below10° C., and the slurry of boronic acid was warmed to room temperature.Water (160 mL) was added over 20 minutes, and the resulting suspensionwas stirred for 2 hours at room temperature. The solid was filtered,washed with IPA/H₂O/Et₃N 50:50:2 (2×50 mL) and dried under reducedpressure at 40° C. until constant weight to give 47.0 g of IRB-07 as the1:0.5 THF—H₂O solvate (off-white solid) that was used without additionalpurifications. The yield was 92%, with a purity of 94.5%.

Example 1D. Preparation of 2-butyl-3-[2′-(triphenylmethyltetrazol-5-yl)-biphenyl-4-yl methyl]-1,3-diazaspiro[4.4]non-1-ene-4-one (IRB-03)

Weight, Mw volume mmol Eq. 2-butyl 1,3-diazaspiro[4.4]non- 363.3  0.96 g2.64 1.0 1-ene-3-(4-bromobenzyl)-4- one (IRB-05) IRB-07-THF-0.5 H₂O513.3  1.42 g 2.77 1.05 Pd(OAc)₂ 224.49  5.7 mg 0.026 1.15Triphenylphosphine 262.5  27.3 mg 0.104 1,2-Dimethoxyethane    8 mL THF   2 mL Potassium carbonate 138.21 0.912 g 6.60 2.5 Water 18.0 0.119 mL6.60 2.5

A mixture of DME and THF was degassed by vacuum/nitrogen purges (3times) and Ph₃P was added in one portion. After the triphenylphosphinedissolved, Pd(OAc)₂ was added, and the yellow-green mixture was degassedagain (2 times), and stirred for 30 min at room temperature. IRB-07 wassuspended, and stirring was continued for 10 min at room temperature.The water was added, and the slurry was stirred for additional 30 min.Powdered K₂CO₃ and IRB-05 were then added sequentially and the resultingmixture was degassed (3 times), and refluxed (approx. 80° C.) for 3hours (TLC monitoring: Hex/EtOAc 2:1). The solvents were evaporatedunder reduced pressure, and toluene (20 mL) and water (20 mL) wereadded. After separation, the aqueous phase was extracted with toluene(10 mL) and the combined organic phases were washed with water andbrine, dried over Na₂SO₄ and evaporated under reduced pressure to give2.1 g of the semisolid residue. The crude material was crystallized fromIPA (15 mL) to give 1.6 g of IRB-03 as a white solid. The yield was 90%,with a purity of 98%.

Example 1E. Preparation of Irbesartan (IRB-00)

Weight, Mw volume mmol Eq. IRB-03 670.84  1.0 g 1.49 1 HCl, 3N  1.5 mL4.5 3 Acetone   3 mL KOH, 85% 56.11 0.42 g 5

IRB-03 (as produced in Example 1D) was dissolved in acetone and 3N HCl,and stirred for 2 hours at room temperature (TLC or HPLC monitoring). Asolution of KOH in 3 mL of water was slowly added, and acetone wasevaporated under reduced pressure. The precipitate (Trityl alcohol) wasfiltered and washed with water (2×5 mL). The combined aqueous filtratewashed with 5 mL of ethyl acetate, and slowly acidified to pH 4 with 3Naqueous HCl. The resulting suspension was cooled down to 0–4° C.,stirred for additional 30 min and filtered. The cake was washed severaltimes with water and dried under reduced pressure at 50–60° C. The yieldwas 0.58 g of IRB-00.

1. A process of making 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid comprising the steps of: a) combining 5-phenyl-1H-tetrazole with chlorotriphenylmethane in the presence of a solvent and a first base; b) combining the product of step a with a borate, in the presence of a solvent and a second base; and c) recovering 2-(5-tetrazoyl)phenylboronic acid.
 2. The process of claim 1, wherein the solvent is tetrahydrofuran.
 3. The process of claim 1 wherein the first base is triethylamine, and the second base is butyllithium. 